SAN FRANCISCO – Mar. 28, 2001 (cancerfacts.com) -- Researchers have found that children are protected against different types of leukemia depending on which form of an enzyme they have for processing a common vitamin. The discovery highlights the impact even minor genetic variation can have on disease, and also shows how distinguishing subtle disease differences can help reveal causes that would otherwise be masked, the scientists say.

Lead author of the study, Dr. Joseph Wiemels, assistant professor of epidemiology and biostatistics at the University of California, San Francisco presented his team's findings at the annual meeting of the American Association for Cancer Research. The study also appears in the Mar. 27 Proceedings of the National Academy of Sciences.

"Although the causes of childhood leukemia are essentially unknown, we have implicated folic acid in this serious disease for the first time," Wiemels said in a prepared statement.

Cancer biologists recognize at least three subtypes of childhood leukemia, based on different abnormalities in the chromosomes and until now, there has been no indication that these three leukemia subtypes develop in different ways.

In one type, known as hyperdiploid, children have extra copies of chromosome 21 as well as other chromosomes. Two other forms, known as translocation subtypes, are characterized by abnormal chromosomes formed during development of the blood cells before the child is born. Each subtype has a different prognosis and treatment protocol, but causes remain unknown and treatments often create other serious medical problems.

In the new study funded by the Kay Kendall Leukemia Fund and the Leukemia Research Fund, Wiemels, in collaboration with colleagues in England and Scotland, focused on molecular differences that define these distinct types of childhood leukemia.

They classified 253 British childhood leukemia patients into one of the three categories by examining the children's DNA using gene-sequencing techniques to determine which of three common forms of the enzyme, MTHFR, each child had. The enzyme is one of two dozen in the body involved in metabolizing the vitamin folic acid.

The scientists discovered that vulnerability to one type of the cancer or another depends on something as simple as which form of the enzyme a child inherits that is needed to process or metabolize folic acid. This member of the vitamin B family is found in fresh fruits and vegetables and is critical to prevent abnormal nerve development in the fetus and colon cancer and heart disease in adults.

Folic acid is shunted through several biochemical pathways in the body, and scientists already knew that inadequate amounts of the vitamin - due to low dietary supply or poor performance by enzymes that metabolize it - leads to defects in the way DNA is replicated in the cells. The consensus on the vitamin's benefits led the FDA in 1997 to require folic acid enrichment in flour and corn products in the United States.

"We know that inadequate folic acid in the body leads to improper DNA replication, and that this may increase cancer risk," Wiemels said. "Earlier studies have shown that low-functioning alleles (variations) of MTHFR prompt the body to set aside more folic acid for DNA synthesis -- probably a trait that evolved as insurance against major DNA damage in times of folic acid undernourishment, which is common during pregnancy.

In the PNAS paper, the researchers report finding that children with a "low-functioning variant" of MTHFR -- one that is relatively poor at metabolizing folic acid -- appear to be protected against one of the translocation-type leukemias, known as MLL. A different low-functioning variant appeared to be protective against hyperdiploid leukemia, they reported.

"Now we have shown that the low-functioning allele protects against the MLL leukemia subtype. It is likely that by assuring adequate folic acid for DNA processing, the enzyme variant is helping to prevent DNA breakage that would lead to MLL translocations."

The situation is somewhat different for hyperdiploid leukemia: In this case a second low-functioning variant of MTHFR protects against this leukemia subtype, probably by altering a second biochemical pathway by which folic acid affects DNA or chromosome structure, Wiemels said.

The United States is among the countries with the highest rates of childhood leukemia in the world, Wiemels said, with about 3,500 children in the U.S. developing the cancer each year.

"Our research suggests that scrutiny of genetic changes in leukemia cells -- at the DNA level -- can reveal potential causes specific to each type of leukemia," Wiemels said.

Although the United States now assures adequate folic acid in the diet by supplementing flour and corn products the new findings may help explain the historically high level of childhood leukemia in California in general and among Hispanic populations in particular.

Hispanic Americans have historically had the highest U.S. rates of newborns with neural tube defects and similarly higher-than-normal rates of childhood leukemia. While use of folic acid supplements before and during pregnancy is increasing among this high-risk group, its use still lags somewhat, Wiemels said, and should be increased to avert childhood diseases.

Wiemels expects that the research will lead to more scrutiny of the role of folic acid and folic acid metabolism in causing childhood leukemia.

"Future studies may suggest methods to exploit folic acid biochemical pathways to treat leukemia," he said.

SOURCE: University of California at San Francisco press release

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